molecules Review Biosynthesis and Biological Activities of Newly Discovered Amaryllidaceae Alkaloids Seydou Ka 1 , Manoj Koirala 1, Natacha Mérindol 1 and Isabel Desgagné-Penix 1,2,* 1 Department of Chemistry, Biochemistry and Physics, Université du Québec à Trois-Rivières, 3351, boul. des Forges, C.P. 500, Trois-Rivières, QC G9A 5H7, Canada; [email protected] (S.K.); [email protected] (M.K.); [email protected] (N.M.) 2 Groupe de Recherche en Biologie Végétale, Université du Québec à Trois-Rivières, 3351, boul. des Forges, C.P. 500, Trois-Rivières, QC G9A 5H7, Canada * Correspondence: [email protected] Received: 4 August 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: Alkaloids are an important group of specialized nitrogen metabolites with a wide range of biochemical and pharmacological effects. Since the first publication on lycorine in 1877, more than 650 alkaloids have been extracted from Amaryllidaceae bulbous plants and clustered together as the Amaryllidaceae alkaloids (AAs) family. AAs are specifically remarkable for their diverse pharmaceutical properties, as exemplified by the success of galantamine used to treat the symptoms of Alzheimer’s disease. This review addresses the isolation, biological, and structure activity of AAs discovered from January 2015 to August 2020, supporting their therapeutic interest. Keywords: Amaryllidaceae alkaloids; specialized metabolism; biosynthesis; antitumor; anti-cholinesterase; antiviral; antiparasitic 1. Introduction The Amaryllidaceae species, belonging to the Asparagales monocot order, are a class of herbaceous, perennial, and bulbous flowering plants. The Amaryllidaceae plant family contains 85 genera and 1100 species that are widely distributed in the tropic and warm temperate regions of the globe [1]. In addition, the Amaryllidaceae plants are cultivated and exploited as ornamental plants for their beautiful flowers [2]. For centuries, Amaryllidaceae have been used in traditional medicine, such as the oil extracted from the daffodil Narcissus poeticus, used to treat uterine tumors [3]. Since the isolation of lycorine in 1877 (initially named narcissia) from Narcissus pseudonarcissus and in 1897 from Lycoris radiata [4–6], the structures of hundreds of Amaryllidaceae alkaloids (AAs) have been elucidated [1,3,7]. They are exploited for their wide range of biological potentials including antitumor, antiviral, antibacterial, antifungal, antimalarial, anti-acetylcholinesterase (anti-AChE), analgesic, and cytotoxic activities [8,9]. Currently, in terms of commercial success, galantamine, widely occurring in the Amaryllidaceae plants, has been approved as an AChE inhibitor by the United States Food and Drug Administration to treat the symptoms of Alzheimer’s disease (AD) [10]. Moreover, several other AAs, including lycorine, haemanthamine, and narciclasine have been used as lead molecules for anticancer research [11]. Thus, AAs represent an important resource for drug discovery. This review addresses the isolation, biosynthesis, biological activities and structure activity of AAs discovered from January 2015 to August 2020. 2. Classification of Amaryllidaceae Alkaloids Todate, more than 650 AAs have been reported, and their chemical library is still expanding [1,12–24]. Although diverse in structure, this plethora of AAs are categorized together as they share a common Molecules 2020, 25, 4901; doi:10.3390/molecules25214901 www.mdpi.com/journal/molecules Molecules 2020, 25, 4901 2 of 27 initial synthesis pathway. In previous literature, large numbers of AAs have been classified into different groups according to chemical characteristics, e.g., molecular skeleton and ring structure [1,3,8,25]. For this review, AAs were classified into 10 main groups instead, following a biochemical classification based on biogenetic lineage and ring type, to easily track the biosynthetic pathways [26] (Table1, Figure1). For example, haemanthamine and crinine were grouped together with respect to their biosynthetic origin and ring type even if they were previously categorized separately [11]. Some AAs with ring types different than those of group I to IX were classified in group X (or other-types) because they follow distinct biogenetic pathway, or because we cannot clearly indicate their biosynthetic origin (Table1). Galanthindole contains a non-fused indole ring and might represent an artifact of homolycorine- or of pretazettine-type derivatives [27]. Ismine is considered to be a catabolic product from the haemanthamine-type skeleton, thus not a specific type of AA [28]. The latter examples demand further investigation on biogenetic origin and are not yet included on any particular type of AA. Table 1. Main types of Amaryllidaceae alkaloids grouped according to their ring type and biosynthetic origin. Number Type Name Ring-Type I Norbelladine N-(3,4-Dioxybenzyl)-4-oxyphenethylamine II Cherylline Tetrahydroisoquinoline III Galantamine 6H-Benzof,f]-2-benzazepine IV Lycorine Pyrrolo[d,e]phenanthridine V Homolycorine 2-Benzopyrano-[3,4-g]indole VI Crinine 5,10b-Ethanophenanthridine VII Narciclasine Lycoricidine VIII Pretazettine 2-Benzopyrano [3,4-c]indole IX Montanine 5,11-Methanomorphanthridine X Other Different ring types and biogenetic origin Molecules 2020, 25, x FOR PEER REVIEW 3 of 28 OH OH HO O HO H3CO H3CO NH HO N HO CH3 N CH3 Norbelladine Cherylline Galanthamine OH N HO H C 3 H H OH H H CO O 3 H O H O N H3CO H O N O O Lycorine Homolycorine Crinine OH OCH3 HO OH H OCH3 O OH N CH3 O NH O H O O O OH H OH O O N OH Pancratistatin Pretazettine Montanine Figure 1.FigureRepresentative 1. Representative Amaryllidaceae Amaryllidaceae alkaloid alkaloid structure structure for forthe themain main Amaryllidaceae Amaryllidaceae alkaloid alkaloid (AA)-types. (AA)-types. Some types of AA, such as plicamine and secoplicamine, are extracted in trace amounts exclusively from specific Amaryllidaceae species, such as Zephyranthes, but are classified in type X as they are rare, dinitrogenous members of AA, with a distinct biosynthetic linage [28–31]. Mesembrine alkaloids (also known as sceletium) have a distinct biosynthetic pathway, without norbelladine as key intermediate, they are usually extracted from Aizoaceae, but can be collected from several species of Amaryllidaceae [20]. Here, we concentrated exclusively on AAs that were discovered since 2015; hence, some alkaloids families are not represented. 3. Biosynthesis of Amaryllidaceae Alkaloids Biosynthesis of AAs with their diverse and complex carbon skeleton involves a sequence of biochemical reactions such as oxidation, reduction, hydroxylation, methylation, phenol-phenol coupling, and oxide bridge formation. Although the complete AA biosynthetic pathway has not yet been elucidated, several steps with catalyzing enzymes can be predicted on the basis of the reaction types and enzyme families [2,26,32,33]. Here, we briefly discuss the AAs biosynthesis pathway and the enzymes involved. Although novel AAs are still being discovered, radiolabeling experiments demonstrated that they all share a common biochemical pathway with a key intermediate; norbelladine, which is subsequently O-methylated, and then undergoes cyclization to give diverse basic skeletons of AAs (Figure 1; Figure 2) [34–40]. Norbelladine originates from the condensation of tyramine and 3,4- dihydroxybenzaldehyde (3,4-DHBA), molecules derived from the aromatic amino acids L-tyrosine and L-phenylalanine, respectively (Figure 2). The enzyme responsible for tyramine biosynthesis is the Molecules 2020, 25, 4901 3 of 27 Some types of AA, such as plicamine and secoplicamine, are extracted in trace amounts exclusively from specific Amaryllidaceae species, such as Zephyranthes, but are classified in type X as they are rare, dinitrogenous members of AA, with a distinct biosynthetic linage [28–31]. Mesembrine alkaloids (also known as sceletium) have a distinct biosynthetic pathway, without norbelladine as key intermediate, they are usually extracted from Aizoaceae, but can be collected from several species of Amaryllidaceae [20]. Here, we concentrated exclusively on AAs that were discovered since 2015; hence, some alkaloids families are not represented. 3. Biosynthesis of Amaryllidaceae Alkaloids Biosynthesis of AAs with their diverse and complex carbon skeleton involves a sequence of biochemical reactions such as oxidation, reduction, hydroxylation, methylation, phenol-phenol coupling, and oxide bridge formation. Although the complete AA biosynthetic pathway has not yet been elucidated, several steps with catalyzing enzymes can be predicted on the basis of the reaction types and enzyme families [2,26,32,33]. Here, we briefly discuss the AAs biosynthesis pathway and the enzymes involved. Although novel AAs are still being discovered, radiolabeling experiments demonstrated that they all share a common biochemical pathway with a key intermediate; norbelladine, which is subsequently O-methylated, and then undergoes cyclization to give diverse basic skeletons of AAs (Figure1; Figure2)[ 34–40]. Norbelladine originates from the condensation of tyramine and 3,4-dihydroxybenzaldehyde (3,4-DHBA), molecules derived from the aromatic amino acids l-tyrosine and l-phenylalanine, respectively (Figure2). The enzyme responsible for tyramine biosynthesis is the tyrosine decarboxylase (TYDC) (Figure2). Two gene transcript variants of TYDC, named TYDC1 and TYDC2, were identified from the transcriptome of different Amaryllidaceae species including N. pseudonarcissus [41], Narcissus papyraceus